Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.
Over 60% of patients in the USA will receive radiation treatment during an illness, and these 600,000 or so individuals will make over 20 million radiation therapy visits, with each patient receiving, on average, 30 treatments of external beam radiation therapy with curative intent. Breast, lung and prostate cancer patients make up over 50% of all patients receiving radiation therapy (American Society for Radiation Oncology, ASTRO, 2012).
The clinical decision to treat “cancer patients” with radiation, or to avoid the use of this therapeutic modality, is currently based on a mixture of subjective, empirical and historical practice, commonly encapsulated within medical “art”. The treatment and management decisions initially involve the suitability of the patients for definitive surgery, their age, extent of cardiopulmonary reserve, defined co-morbidities, the pathological grade of the tumour, and the stage of the disease as determined by various imaging modalities such as MRI, fMRI, CT, ultrasound, X-ray, PET, and combinations thereof. There is minimal quantitative input in terms of the properties of the tumour itself, with pathologists interpreting how tumourous cells “look” in terms of their morphological deviation from normal cells, the differences that are apparent in tumor architecture from that of normal tissues, and the extent of cell division within microscopic fields.
More specifically, the assessment of whether an individual is suspected of having a tumour or a cancer that requires treatment currently depends upon pathological examination of a sample of tissue, organ or blood sample. The results of the pathology uniquely determine the flow-on clinical events that are part of the current conveyor belt of medical art. In the United States of America (USA), more than 60% of cancer patients receive some form of radiation treatment, usually in combination with surgery and systemic therapies involving selected drugs, and more recently in combination with immunotherapies. The critical decision on whether a patient should, or should not, receive radiation, depends first and foremost on the report made by a pathologist (Davidson and Rimm; JAMA; 313; 1109-1110; 2015. Elmore et al., JAMA; 313; 1122-1132. 2015). This report is the current basis upon which a determination of patient management is made, which is usually carried out in a multidisciplinary setting involving radiation oncologists, medical oncologists and surgeons. However, such a critically important decision currently relies on a pathological diagnosis primarily based on the subjective analysis also described above, concerning cellular morphology and tissue architecture of formalin-fixed paraffin-embedded and Hematoxylin and Eosin (H&E) stained tissue sections (see FIG. 1, for example).
The concordance among pathologists of diagnostic interpretation is variable, and depends on the type of tumour under investigation. In the case of atypical hyperplasia of the breast, the concordance is only 48% (Elmore et al., JAMA, 313; 1122-1132. 2015). In terms of tumours of the thyroid, for example, it is very difficult to discriminate between normal tissue and “cancerous” tissue, except with very late stage tumours. This subjectivity of interpretation of the pathology results in overtreatment of those patients who achieve little benefit from radiotherapy, but suffer its well known harms, and results in under treatment of those patients who could benefit from radiation, but do not receive it. To avoid legal issues, physicians err on the side of caution, and radiation is given to many patients in the absence of any quantitative evidence of benefit, in the belief that following surgery, for example, radiation will minimize the effects of any residual cancer cells that have been left behind in the margins surrounding the resected tumour. For those patients whose tumours and associated stromal niches have some degree of radio-resistance, the radiation therapy is futile, since even if some radiation sensitive cells are killed, the surviving tumour and stromal cell populations have been selected for even more radio-resistance.
Medical practitioners generally rely upon evidence-based clinical decision support resources such as at the World Wide Web at uptodate.com. This resource provides a current clinical summary of radiation therapy techniques in cancer control at multiple levels, including types of radiation such as external beam radiotherapy, brachytherapy, intraoperative radiotherapy and targeted radionuclide therapy.
The Coverage and Analysis Group at the Centers for Medicare and Medicaid Services (the federal agency within the US Department of Health and Human Services) requested an assessment report on prostate cancer that was provided by Ip et al., 2010, at the Tufts Evidence-based Practice Center under contract to the Agency for Healthcare Research and Quality (RHQ), Rockville, Md., USA. (contract #290 2007 10055 I). This report addressed the evidence for the clinical and biochemical outcomes of different radiotherapies, such as stereotactic body radiation therapy, fractionated external beam radiation therapy and brachytherapy, on patients with localized prostate cancer (T1 and T2 disease). The external beam radiation therapies (EBRT) include intensity-modulated radiotherapy, conformal radiation, stereotactic body radiation, CyberKnife and proton beam radiation, while brachytherapy includes permanent implantation of radioactive isotopic “seeds” as well as temporary high dose radioactivity seeds.
The type of radiation delivered to a patient was also evaluated, whether it was photon or proton based, and whether the radiation was delivered via a linear accelerator, gamma rays (from a Cobalt-60 source), or via radioactive seeds comprising 125Iodine, 131 Cesium or 103Palladium, for Low Dose Rate Brachytherapy (LDRBT); or 192Iridium (for High Dose Rate Brachytherapy (HDRBT). The evaluation also included the parameters that impinged on patient outcomes including radioactive dosages, adverse events, treatment planning algorithms, and the number of fractions delivered.
The rating system used by Ip et al. to evaluate the various clinical trials in terms of the strength of evidence emerging from any trial, was a subjective 3-tier one: high, moderate and insufficient.
In terms of the benefits versus harms of different radiotherapies, the results were as noted below.
In terms of the comparison of the benefits versus harms of radiotherapies, versus no radiation treatment, the strength of the evidence was found to be of category 3, insufficient.
The strength of the evidence was found to be insufficient for patient survival, when low dose rate brachytherapy was compared to external beam radiation therapy.
The strength of the evidence was found to be insufficient for biochemical control, when brachytherapy was compared to external beam radiation therapy and when high dose rate brachytherapy was compared to low dose rate brachytherapy.
The strength of the evidence was found to be insufficient for genitourinary and gastrointestinal toxicities, when low dose rate brachytherapy was compared to external beam radiation therapy.
The strength of the evidence was found to be insufficient for various combination therapies, LDRBT plus EBRT.
The strength of the evidence was found to be insufficient for different studies within the Stereotactic Body RadioTherapy (SBRT) and EBRT umbrellas, namely bladder and rectal toxicities, freedom from biochemical failure and genitourinary or gastrointestinal toxicities.
The strength of the evidence was found to be insufficient for low dose rate brachytherapy in terms of radioactive seed comparisons, 125Iodine and 103Palladium.
The strength of the evidence was found to be insufficient for the contribution of age, race, ethnicity, co-morbidities, treatment-related adverse effects and disease progression to the baseline risk of a patient as a contributor to the outcome from radiotherapy.
The detailed report of Ip et al., 2010, concluded that in one of the two most extensively studied tumour types (localized prostate and localized breast), the evidence for the benefits of radiotherapy compared to no treatment for men with T1 or T2 prostate “cancer” revealed no quantitative indicators for radiation treatment of patients. Furthermore, there was substantial heterogeneity within and between studies, with many of the findings in this large evaluation being inconsistent.
The Ip et al. report indicates that the underlying risk of progression of the disease to the metastatic state varies widely between patients. The inability to objectively determine risk of progression means that patients deemed to be at “low” risk are advised to undergo brachytherapy, whereas those deemed to be at “intermediate” risk tend to be given external beam radiotherapy.
There is therefore an urgent need to identify those patients who have a biological parameter that favours one treatment modality compared with another, e.g., tumour characteristics that are favourable for radiation treatment, namely those whose tumours are sensitive to radiation versus those patients whose tumours are more radiation resistant, and therefore should be spared radiation treatment which is likely to be futile and harmful.
There is a further need for identifying biological parameters that might be useful in distinguishing characteristics of the abnormal tumour cells themselves, and the characteristics of the stroma, and the three dimensional (3D) distribution in which such abnormal cells are embedded. For example, a tumour that has abnormal cells evenly spread within a stromal component, is very different to a tumour where the abnormal cells are largely separate from stromal cells. In the case of prostate cancer, both of these situations occur within different foci of abnormal cells within the gland itself and also within metastases to bone. No current external imaging methods (MRI, CT or 18FDG imaging methods) can reliably identify these different areas, or their different characteristics.
To date, there are no available data pertaining to the use of radiotherapy for a given tumour of a particular patient: current data have no solid quantitative basis.
There remains a need for assays that provide quantitative indicators that enable the identification of a biological parameter in a sample, e.g., radio-sensitivity or radio-insensitivity/radio-resistance when making a suitable decision in respect of treating patients such as whether or not to treat “cancer patients” with radiation, or to avoid the use of radiation.
It is an objective of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art treatments or/and to provide a useful alternative.